Abstract 3862: Left Ventricular Pre-excitation in Tbx2 Deficient Mice
Background. Circus movement tachycardias frequently occur in Wolff-Parkinson-White patients. In these patients an aberrant electrical connection between the atrial and ventricular wall is present. This accessory pathway causes pre-excitation of the ventricular wall during normal sinus rhythm. In development, Tbx2 is expressed in the atrioventricular canal (AVC) where it represses working myocardial genes including Cx40. Tbx2 deficiency causes ectopic working myocardium differentiation specifically in the left side of the AVC. We investigated whether this working myocardium serves as an accessory pathway as is seen in the pre-excitation syndrome Wolff-Parkinson-White in humans.
Methods. Hearts were isolated from Tbx2 mutant mice at embryonic day 17.5. Each heart was incubated for 5 minutes with Tyrode’s solution containing the fluorescent dye Di-4 Anneps. Subsequently, the heart was placed in an inverted microscope set-up and action potentials were recorded by optical mapping. Atrioventricular conduction time was defined as the time difference between the first moment of activation on the atrium and the first moment of activation on the ventricle. Also, expression of Cx40, Cx43 and Scn5a in the AVC of wildtype and Tbx2 deficient fetuses was measured by immunohistochemistry.
Results. In fetal wild-type hearts, the AV conduction time was 73 +/− 9 ms (n=5) during sinus rhythm. Tbx2 deficient embryos exhibited either pre-excitation of the left ventricle (AV-time of 9 ms, n=1) or normal AV-delay followed by retrograde activation of the left atrium (n=2). Furthermore, Cx40, Cx43 and Scn5a were ectopically expressed in the AVC of Tbx2 deficient fetuses.
Conclusion. The absence of Tbx2 causes ectopic expression of Cx40, Cx43 and Scn5a in the AVC which leads to a functional accessory connection between the left atrial and the left ventricular myocardium. This suggests that deficiencies in Tbx2 or factors upstream of Tbx2 could be involved in the Wolff-Parkinson-White syndrome.